Despite the presence of tumor-specific T cells in patients, tumors progress. Over two decades of clinical trials of vaccines or T cell transfer therapy have resulted in inconsistent efficacy, but have begun to reveal the complexity and the requirements for eliciting an effective tumor-specific T cell response. The broad diversity of T cell responses in the tumor-bearing host includes subsets with both effective and inhibitory functions, helping to explain why increasing the number of tumor-specific T cells may not have the desired effect. A recently-described uncommitted CD4 memory T cell subset, Thpp, may have both positive and negative effects on anti-tumor immunity. Potential positive functions include high proliferative potential, and the ability to generate CD4 effector cells and help to generate CD8 effectors. The potential negative function is the expression of CD73, which generates the immunosuppressive mediator adenosine. In this proposal, two predictions regarding the potential positive and negative roles of Thpp cells in anti-tumor responses will be tested: First, that CD73 expressed by Thpp cells (and other T cell subsets) will inhibit an effective anti-tumor immune response; and second, Thpp that do not express CD73 will enhance anti-tumor immunity by proliferating extensively and differentiating into effectors, or helping effector responses. Confirmation of both of these hypotheses would help to design strategies to amplify the beneficial anti-tumor T cell functions and reduce suppressive T cell activities. This proposal addresses the need to understand the positive and negative influences of CD4 T cells on generating and sustaining an effective immune response that can eradicate tumors and prevent their recurrence. There are nearly 1.5 million cases of cancer diagnosed each year and this research will generate insight into how to design vaccines and immunotherapy for cancer. [unreadable] [unreadable] [unreadable]